KR20060109903A - Nasal Release Control Delivery System - Google Patents

Abstract

The present invention provides an active ingredient in a sustained manner that can provide better bioavailability and longer duration of action, even in preparations that can be administered nasally for controlled release of sex hormones, particularly at very low doses. For formulations that are intended to be absorbed.

Description

Controlled release delivery system for nasal applications

The present invention relates to a formulation for controlling the release of sex hormone in the body circulation after nasal administration. Nasal drug delivery offers many advantages including rapid adsorption by abundant capillaries, rapid onset of action, avoidance of first-pass metabolism in the liver, efficacy of chronic drug treatment, and ease of administration.

Unlike macromolecules and / or ionized molecules, it is known that lipophilic pharmaceutical compounds of sufficiently low molecular weight are generally readily adsorbed by the nasal mucosa. For these drugs it is possible to obtain pharmacokinetic properties similar to those by intravenous injection.

However, due to the rapid mucociliary clearance at the deposition site, it is difficult to keep the concentration of the therapeutic drug constant for a long time because of the reduced adsorbable time of the therapeutic agent and the presence of enzymes capable of degrading the therapeutic agent in the nasal cavity.

There have been many efforts to overcome this limitation, including the use of bioadhesive systems that increase the retention time in the nasal cavity, the use of enhancers to improve the permeability of the nasal mucosa, or the use of stabilizers to prevent degradation of the drug.

For example, Illum proposed the use of bioadhesive microspheres in GB 1987000012176 and WEST Pharmaceutical proposed the use of in-situ gelled pectin formulations in PCT / GB98 / 01147.

Studies on the nasal adsorption of a rather small, lipophilic sex steroid compound confirmed that the sex steroid compound is readily adsorbed by the nasal mucosa and rapidly delivered to the serum. Because of this and the short half-life and limited potential for sustained release nasal administration, the clinical use of these compounds has been limited until now, because hormone replacement therapy generally requires long-term administration.

Several formulations have been proposed for these drugs. In other words, in the case of testosterone, which is almost insoluble and somewhat soluble in vegetable oil, Hussain et al. Described "Testosterone 17β-N, N-dimethylglycinate hydrochloride: A prodrug with a potential for nasal delivery of testosterone", J. Pharmaceut. Sci. 91 (3): 785-789 (2002), argued that testosterone would be suitable for nasal administration if it could increase solubility in water. Hussain proposed the use of the water-soluble drug precursor testosterone 17β-N, N-dimethylglycinate, which took 12 minutes (at 25 mg dose) and 20 minutes to reach the highest plasma concentration corresponding to intravenous administration. (50 mg dose) and a drug elimination half-life of about 55 minutes. Even in this case, this rate is not essential because sex hormone replacement therapy is not an emergency treatment.

Ko et al., "Emulsion formulations of testosterone for nasal administration", J. Microencaps. , 15 (2): 197-205 (1998)], charged testosterone submicron O / W emulsion formulations based on the hypothesis that drug uptake can be enhanced by dissolution of the drug and / or prolongation of the residence time in the nasal cavity. (Water / Tween80, Soybean Oil / Span80). Ko confirmed that the relative bioavailability of the positively charged (55%) and negative (51%) charged emulsions was greater than that of the neutrally charged emulsions (biological availability = 37%). Tmax (time to peak concentration) was observed at about 20 minutes after administration in all three cases. The graph shows that the concentration after intravenous administration (aqueous alcohol solution) shows the longest half-life, but it is not possible to evaluate the difference in serum concentrations as Ko did not collect blood samples prior to dosing. it's difficult. In practice, the emulsion is not suitable because the droplet size (430 nm) is not suitable for nasal administration.

Although the solubility of progesterone in water and oil is somewhat similar to that of testosterone, the researchers' approach was different:

Cicinelli et al., "Progesterone administration by nasal spray", Fertil Steril 56 (1): 139-141 (1991), "Nasally-administered progesterone: comparison of onitment and spray formulations", Maturitas 13 (4): 313-317 (1991), Progesterone administration by nasal sprays in menopausal women: comparison between two different spray formulations, Gynecol Endocrinol 6 (4): 247-251 (1992), "Effects of the repetitive" administration of progesterone by nasal spray in postmenopausal women ", Fertil Steril, 60 (6): 1020-1024 (1993) and" Nasal spray administration of unmodified progesterone: evaluation of progesterone serum levels with three different radioimmunoassay techniques ", Maturitas 19 (1): 43-52 (1994)], when progesterone dissolved in almond oil (20 mg / ml) was administered by nasal spray, the bioavailability of progesterone dissolved in dimethicone or PEG-based ointment was increased. Higher It was confirmed. Cmax (maximum blood concentration) was observed after 30 to 60 minutes after nasal administration of progesterone dissolved in almond oil, and the concentration rapidly decreased after 6 to 8 hours after a single administration.

Steege et al. Found that Tmax was 30 minutes when progesterone was dissolved (200 mg / ml) in polyethylene glycol in "Bioavailability of nasally administered progesterone", Fertil Steril, 46 (4): 727-729 (1986). . The duration of serum concentration was more than 8 hours but the concentration variation was large.

However, Tmax was only 5.5 minutes when formulated with progesterone using ethanol / propylene glycol / water (Kumar et al., "Pharmacokinetics of progesterone after its administration to ovariectomized rhesus monkeys by injection, infusion, or nasal spraying", Proc. Natl.Acad. Sci. USA, 79: 4185-9 (1982).

Provasi et al., "Nasal delivery progesterone powder formulations comparison with oral administration", Boll. Chim. Farm. 132 (10): 402-404 (1993)], the Tmax of progesterone-containing powder mixtures (freeze-dried progesterone / cyclodextrin after co-polishing) was found to be within 2 to 5 minutes, and the serum concentration was At about 20 minutes already decreased.

The results are quite similar to the case of already commercially available water soluble nasal sprays containing estradiol formulated in testosterone (see above) and cyclodextrin (Aerodiol ^® ). The maximum serum concentration attainment time is within 10-30 minutes and after 2 hours it decreases to 10% of the maximum value. Again, this rate is not essential in sex hormone replacement therapy and is undesirable given the short half-life of the hormone.

In addition to the problems of "free / adsorption" mentioned above, in relation to sex hormones and bioavailability, liver metabolism and short half-life remain very important issues and also have high protein binding properties. Approximately 40% of blood testosterone binds to, for example, sex hormone binding globulin (SHBG) (2% in men, up to 3% in women remains unbound (free)) and the rest is albumin and its Combine with other proteins outside. Testosterone bound to albumin is easily dissociated and is believed to have biological activity, while testosterone binding to SHBG does not. However, the amount of SHBG in plasma determines the distribution of free and bound testosterone, and the free testosterone concentration determines (limits) the half-life of the drug. Accordingly, there is a need for a safe, stable and easy to manufacture sex hormone drug formulation system that can be administered to the nasal cavity of a patient to provide a therapeutic effect.

Summary of the Invention

The inventors of the present invention have conducted intensive studies on various sex hormone drug formulations and surprisingly, incorporation of the drug into a particular lipophilic or partial lipophilic system generally prolongs the duration of serum concentrations in plasma, resulting in higher bioavailability and It was found that better serum concentration characteristics could be obtained.

The present invention provides a pharmaceutical composition comprising a) one or more sex hormone drugs; b) one or more lipophilic or partially lipophilic carriers; And c) a compound or mixture of compounds having a surface tension reducing activity, which is contained in an amount effective for in situ formation of the emulsion upon contact of the formulation with water.

Preferably, the lipophilic carrier comprises an oil.

More preferably, the oil is vegetable oil.

Most preferably, the oil is castor oil.

In a preferred embodiment of the invention the oil is 30 to 98% by weight, preferably 60 to 98% by weight of the formulation, more preferably 75 to 95% by weight, more preferably 85 to 95% by weight, most preferably About 90% by weight.

In another embodiment, component (c) is at least one surfactant and / or sorbitol selected from the group consisting of polyhydric alcohols, sorbitan, polyoxyethylene sorbitan, polyoxyethylene, sucrose, lecithin which is a fatty acid ester of polyglycerol , Glycerine, polyethylene glycol, macrogol glycerol fatty acid esters, characterized in that it comprises one or more humectants or mixtures thereof.

Most preferably, component (c) comprises oleyl macrogolglycerides or a mixture of oleyl macrogolglycerides.

Preferably, component (c) is included in the formulation in an amount of 1 to 20% by weight, preferably 1 to 10% by weight, more preferably 1 to 5% by weight, most preferably about 4% by weight. .

Another embodiment includes a viscosity modifier.

Preferably, the viscosity modifier is composed of cellulose and cellulose derivatives, polysaccharides, carbomers, polyvinyl alcohols, povidones, colloidal silicon dioxide, cetyl alcohols, stearic acid, beeswax, petrolatum, triglycerides and lanolin or mixtures thereof Thickeners or gelling agents selected from the group.

Most preferably, the viscosity increasing agent is colloidal silicon dioxide.

Preferably, the viscosity modifier is included in the formulation in an amount of 0.5 to 10% by weight, preferably 0.5 to 5% by weight, more preferably 1 to 3% by weight and most preferably about 3% by weight.

In a preferred embodiment, the sex hormone drug is testosterone.

Preferably, the sex hormone drug is included in the formulation in an amount of 0.5 to 6% by weight, preferably 2 to 4% by weight, more preferably 0.5 to 2% by weight, most preferably about 2% by weight. .

Detailed description of the invention

The resulting formulation is chemically and physically stable and may be a solution or suspension of pharmacologically active substance. It is preferable to fill the formulation in a high viscosity state in an air-blocking, multi-dose device that does not contain preservatives that can be administered at the correct dose.

When the drug or drug particle reaches the absorption site, it must remain at the deposition site for a sufficient time and be absorbed at a predictable rate through the patient's mucosa to block the inactivation by enzyme metabolism and / or binding to the protein. .

Definitions of terms used in the present invention are as follows.

The term “sex hormone drug” refers to one or more sex hormones (eg testosterone), biological drug precursors of one or more sex hormones (eg androstenedione, progesterone and 17-α-hydroxyprogesterone), derivatives of one or more sex hormones (eg Stannolone and 4-chloro-1-dihydromethyltestosterone) or mixtures thereof. In a preferred embodiment said sex hormone drug is testosterone.

Sex hormone drugs are included in the formulation in an amount of 0.5 to 6% by weight, preferably 2 to 4% by weight, more preferably 0.5 to 2% by weight, most preferably about 2% by weight.

Drugs of the invention may also be incorporated into the formulation in processed form, such as microspheres, liposomes, and the like.

The term "lipophilic carrier" refers to vegetable oils such as castor oil, soybean oil, sesame oil or peanut oil, ethyl oleate, oleyl oleate, isopropyl myristate, medium chain triglycerides, fatty acid esters such as glycerol esters or polyethylene glycols, phospholipids And white soft paraffin or hydrogenated castor oil, but are not limited thereto. Especially useful is castor oil.

It is also possible for the drug to be incorporated into the oil mixture.

The specific amount of oil that is an effective amount depends on the type of viscosity modifier (see below) included in the formulation. Therefore, it is not necessary to specify the amount of oil included in the formulation of the present invention. Generally, however, the lipophilic moiety is 30 to 98% by weight, preferably 60 to 98% by weight, more preferably 75 to 95% by weight, even more preferably 85 to 95% by weight of the formulation within the formulation. Preferably in an amount of about 90% by weight.

Component (c) comprises one or more surfactants and / or sorbitol, glycerin, such as, but not limited to, polyhydric alcohols, sorbitan, polyoxyethylene sorbitan, polyoxyethylene, sucrose, lecithin which is a fatty acid ester of polyglycerol One or more humectants, such as polyethylene glycol or macrogol glycerol fatty acid esters. However, oleyl macrogolglycerides (such as Labrafil M 1944 CS, available from Gattefosse (Franco)) are particularly useful.

Incorporation of the drug into the surfactant mixture is also possible.

The specific amount of surfactant to be an effective amount depends on the type of oil or oil mixture (see above) included in the formulation. Thus, it is not necessary to specify the amount of surfactant included in the formulation of the present invention. In general, however, the surfactant may be present in the formulation in an amount of 1 to 20% by weight, preferably 1 to 10% by weight, more preferably 1 to 5% by weight, most preferably about 4% by weight.

The term "viscosity regulator" means a thickener or gel former. Examples thereof include, but are not limited to, cellulose and its derivatives, polysaccharides, carbomers, polyvinyl alcohols, povidones, colloidal silicon dioxide, cetyl alcohols, stearic acid, beeswax, petrolatum, triglycerides or lanolin. Particularly useful, however, is colloidal silicic acid (such as Acrosil 200, available from Degussa).

Incorporation of the drug into the thickener or gel former mixture is also possible.

The specific amount of thickener / gel forming agent that is an effective amount depends on the type of oil or oil mixture (see above) included in the formulation. Therefore, there is no need to specify the amount of thickener / gel former included in the formulation of the present invention. Generally, however, thickeners / gelling agents are present in the formulation in an amount of 0.5 to 10% by weight, preferably 0.5 to 5% by weight, more preferably 1 to 3% by weight and most preferably about 3% by weight. Can be.

The formulations according to the invention can also be powdered, for example by methods such as freeze drying or partial drying.

In general, the formulations of the present invention can be prepared very easily by conventional methods. Examples of formulations are as follows.

● emulsion

Thickeners or gelling agents, together with surfactants if necessary, are added to a sufficient amount of water and dispersed in high speed mixing (mixture 1). Water and / or lipophilic carriers are introduced into the second container, if necessary, with a surfactant (mixture 2). Add hormones to Mixture 2 with extreme care to avoid introducing air. Mixture 2 is added to mixture 1, adjusting pH and tension, if necessary, to homogenize and sterilize the resulting mixture.

● Anhydrous Formulation

The lipophilic carrier and emulsifier are charged into the stirrer and then 75% of the viscosity modifier is mixed. The hormone is added with stirring until a homogeneous dispersion of the active ingredient is obtained. The formulation is then adjusted with the remaining viscosity modifier to the required viscosity.

The formulation is preferably filled into an airtight nasal spray device that does not contain preservatives such as the COMOD system available from Ursatec.

"High biological availability" means that the serum concentration of sex hormones after a single administration is maintained at a concentration sufficiently higher than the reference concentration for 6 hours, more preferably for 8 hours, most preferably for at least 10 hours. .

Since sex hormones are rarely soluble in water, the rate of adsorption of the drug is determined by the rate at which sex hormones are released from the formulation. Surprisingly, the incorporation of sex hormone drugs, such as testosterone, into oily formulations containing suitable surfactants according to the invention, it has been found that the physiological serum concentration of the hormone is obtained and the hormone can continue to function for a long time.

On the one hand, the hormone can be released continuously due to the viscosity of the formulation remaining on the mucosa for a long time and the solubility of the hormone in the oily carrier.

On the other hand, when the formulation is in contact with the moisture of the mucosa, the surfactant forms oil droplets containing the drug, and consequently the precipitation production of the drug is disturbed. Thus, the addition of a suitable surfactant to the formulation yields better and more effective dissolution properties of the hormone, since there is no significant change in the bioequivalence that ensures dissolution properties.

In FIG. 1, the dotted line shows the serum concentration after the most preferred formulation is administered once in the nasal cavity.

The formulations shown below were chosen taking into account the serum concentrations of the resulting active ingredients but also exhibit significant skin protective properties for long term administration.

Table 1 Most Preferred Formulations

compound Content in the container Delivery amount when spraying Testosterone 2% ≒ 2.8 mg Aerosil ^® 200 3% ≒ 4.2 mg Labrafil ^® M 1944 CS 4% ≒ 5.6 mg Castor Oil, Refined Grade 91% ≒ 127.4 mg

Typical serum concentration

Comparing the various formulations containing testosterone (see FIG. 1), the specific oily formulations of the present invention resulted in a marked reduction in Cmax, which can be evaluated as desirable from a toxicological point of view. In addition, the concentration of free testosterone was very constant over 10 hours. This is similar to the physiological release rhythm of testosterone.

In conclusion, the non-administrative formulations of the present invention differ from conventional formulations, in particular in sustained release formulations, because they are similar to the physiological release rhythm of testosterone release. In addition, the formulation can avoid abnormally high or low testosterone concentrations, which does not inconvenience the patient and is useful as a hormone replacement therapy. As shown in FIG. 1 (upper line), a simple nasal spray containing testosterone is not desirable in this respect.

What is disclosed in the above description, claims, and / or drawings is intended to realize the invention in its various forms, independently and in combination.

Claims (14)

In the non-administration formulation, a) one or more sex hormone drugs; b) one or more lipophilic or partially lipophilic carriers; And c) A non-administration formulation comprising a compound or mixture of compounds having a surface tension reducing activity, which is contained in an amount effective for in situ formation of the emulsion upon contact of the formulation with water. The non-administrative formulation of claim 1, wherein the lipophilic carrier comprises an oil. The non-administration formulation of claim 2, wherein the oil is vegetable oil. 4. The nonadministration formulation of claim 3, wherein the oil is castor oil. The method according to claim 2, wherein the amount of oil is 30 to 98% by weight, preferably 60 to 98% by weight, more preferably 75 to 95% by weight, more preferably 85 to 95 of the formulation. Non-administrative formulation, by weight, most preferably about 90% by weight. At least one surfactant selected from the group consisting of lecithin which is a polyhydric alcohol, sorbitan, polyoxyethylene sorbitan, polyoxyethylene, sucrose, polyglycerol fatty acid ester and And / or one or more humectants or mixtures thereof selected from the group consisting of sorbitol, glycerin, polyethylene glycol and macrogol glycerol fatty acid esters. 7. A non-administrative formulation according to claim 6, wherein said component (c) comprises oleyl macrogolglyceride or a mixture of oleyl macrogolglycerides. 8. The composition according to claim 6 and 7, wherein component (c) is 1 to 20% by weight, preferably 1 to 10% by weight, more preferably 1 to 5% by weight, most preferably about A non-administrative formulation comprising 4% by weight. The dosage form of claim 1, further comprising a viscosity modifier. The method of claim 9 wherein the viscosity modifier is composed of cellulose and cellulose derivatives, polysaccharides, carbomers, polyvinyl alcohol, povidone, colloidal silicon dioxide, cetyl alcohol, stearic acid, beeswax, petrolatum, triglycerides and lanolin or mixtures thereof. Non-administration formulation comprising a thickener or gel-forming agent selected from the group. The dosage form of claim 10, wherein the viscosity modifier is colloidal silicon dioxide. The viscosity modifier according to claim 9, wherein the viscosity modifier is 0.5 to 10% by weight, preferably 0.5 to 5% by weight, more preferably 1 to 3% by weight and most preferably about 3% by weight in the formulation. Non-administration formulations included in amounts of%. The dosage form of claim 1, wherein the sex hormone is testosterone. The method according to any one of the preceding claims, wherein the sex hormone drug is in the formulation of 0.5 to 6% by weight, preferably 2 to 4% by weight, more preferably 0.5 to 2% by weight, most preferably about 2% by weight. Non-administration formulations included in amounts of%.

Images